Abstract 6279: Combination of metformin and local irradiation efficiently provokes abscopal effects in a murine rectal cancer model
Authors: Mineyuki Tojo, Hideyo Miyato, Koji Koinuma, Hisanaga Horie, Hidenori Tsukui, Akira Saito, Yuki Kimura, Yuki Kaneko, Hideyuki Ohzawa, Hironori Yamaguchi, Alan Kawarai Lefor, Naohiro Sata, Joji Kitayama
Journal: Cancer Research (2022)

Abstract Introduction; Neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer is effective for the reduction of local recurrence and improvement of postoperative QOL. However, CRT has little effects for metastatic lesions in distant organs and does not prolong the prognosis. Abscopal effect refers to a phenomenon of tumor regression at a distant tumor away from the irradiated primary tumor, presumably through the host immune system. Metformin, a widely used drug for the treatment of type 2 Diabetes Mellitus, has been shown to elicit anti-cancer effects partly through the activation of host immunity. However, how metformin modulates the abscopal effects of local radiation (RT) and metformin has not been well investigated. Method; Mice were subcutaneous inoculated by 1x106 cells of LuM1, a highly murine lung metastatic subclone of colon 26, at right flank of 7 weeks female BALB/c mice which were treated with metformin and/or RT. In RT groups, 4Gy X-ray was selectively given to subcutaneous tumors using lead shield under general anesthesia at day 13 and 15. Metformin hydrochloride (1mg/ml) were orally administrated from day13 continuously. At 28 days, mice were sacrificed, and we evaluated the weight of primary subcutaneous (s.c) tumor and the number of lung metastases. The phenotypes of splenocytes and blood were examined by flowcytometric analysis. Results: Local RT (4Gy x 2) suppressed the growth of s.c tumor to approximately half of control group although not statistically significantly (p=0.067). Metformin alone did not significantly suppress the tumor growth. However, when combined with RT, tumor weight at day28 was markedly reduced as compared with control group (p&amp;lt;0.01). Many lung metastases developed in all control group mice (Median (M)=120, 22-188) which was not changed by the treatment of metformin alone. The number of metastases tended to be reduced in RT group, although not significant (M=34, 3-78, p=0.12). In comparison, when metformin was combined to RT, the number of lung metastasis was markedly decreased (M=13, 0-70, p&amp;lt;0.01) with no metastases detected in 3 in 10 mice. The ratios of CD4(+) or CD8(+) T cells tended to be reduced in mice treated with RT alone, while increased in mice treated with RT and Metformin. CD49b(+)CD335(+) activated natural killer (NK) cells was significantly increase in combination group (1.1%±0.19% vs 2.6%±1.0%, p&amp;lt;0.05). The ratios PD-1(+) cells tended to be reduced, whereas those of IFN-γ (+) cells in T cell subpopulations after stimulation were significantly increased in mice treated with RT and metformin as compared with those in control group (CD4; 6.8±2.4% vs 10.4%±1.3%, p&amp;lt;0.05; CD8; 24.1±3.6% vs 40.4%±7.2%, p&amp;lt;0.01) Conclusion;Metformin restores T cell exhaustion and increase the number of activated NK cells in irradiated mice which may suppress the growth of lung metastases as abscopal effects. Citation Format: Mineyuki Tojo, Hideyo Miyato, Koji Koinuma, Hisanaga Horie, Hidenori Tsukui, Akira Saito, Yuki Kimura, Yuki Kaneko, Hideyuki Ohzawa, Hironori Yamaguchi, Alan Kawarai Lefor, Naohiro Sata, Joji Kitayama. Combination of metformin and local irradiation efficiently provokes abscopal effects in a murine rectal cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6279.